Semaine du cerveau 2016 : conférence inaugurale

Early-born neurons are abnormally positioned in the doublecortin knockout hippocampus

Doublecortin knockout (Dcx KO) mice exhibit hippocampal epilepsy. Anatomically the hippocampus shows abnormally positioned neurons (heterotopia) and the mutant CA3 pyramidal layer is fragmented. Gene expression studies were performed by Khalaf-Nazzal, Stouffer et al (Team 2), using laser capture microdissection to separate the two Dcx KO CA3 neuronal layers (KO-I, KO-E), comparing these to the single layer in wild-type (WT) animals.Comparing all KO cells to WT indicated serious cellular defects, pinpointed by cell stress, metabolism and organelle gene differences. Comparing the two Dcx KO layers between them, and individually to WT, revealed that they differ substantially from each other, and notably show differences in maturity at P0. Testing layer-specific genetic markers revealed a partial inversion of cells in the Dcx KO with normally deeper 'outer boundary' neurons being found superficially in the mutant (in KO-I). Outer boundary neurons are also the earliest-born and bromodeoxyuridine birthdating confirmed that these are abnormally positioned in the Dcx KO brain, with respect to all other neurons.This work, identifying subpopulations of cells in the Dcx KO hippocampus, sheds light on key developmental mechanisms in this little-understood, curved structure. Perturbing anatomical position related to birthdate may contribute to hyperexcitability by affecting morphology and connectivity, cell stress and organelles. This is the first time to our knowledge that gene expression patterns have been used to distinguish the features of abnormally positioned neurons shedding light on their origins. Hum Mol Genet.2016 Dec 22. pii: ddw370. doi: 10.1093/hmg/ddw370. [Epub ahead of print]

GABAergic plasticity in the lateral habenula and cocaine withdrawal

Cocaine withdrawal can produce aversive states and vulnerability to relapse, both hallmarks of addiction. However, the neural circuits and molecular mechanisms underlying these aspects of withdrawal remain elusive. Frank J. Meye and Manuel Mameli show that cocaine withdrawal reduces the vesicular GABA transporter at synapses from pallidum to lateral habenula, thereby decreasing inhibitory transmission. These results, just published in the journal Nature Neuroscience, indicate that GABAergic synaptic plasticity within the lateral habenula is crucial for behaviors modeling cocaine-evoked aversive states and stress-induced relapse.